1. Mechanical Fluid Removal Therapies
Patients that exhibit symptoms of body fluid overload retain excessive amounts of fluid in the abdomen, legs and lungs. For example, excessive fluid in the lungs, referred to as edema, can cause patients to have difficulty breathing. Moreover, edema in the lungs leads to poor blood oxygenation. Poor oxygenation leads to acidosis and deleterious neurological and hormonal phenomena that increases vasoconstriction and load on the heart. In addition, vasoconstriction leads to reduced blood flow to the kidneys and diminishes the effectiveness of the main pharmacological means of fluid removal—diuretic treatment. The reduced blood flow can result in kidney failure.
Different modalities of Continuous Renal Replacement Therapy (CRRT) have been used to treat patients suffering from excess fluid overload and acute renal failure. In the acute condition, CRRT has been performed using standard methods of hemodialysis and continuous arterio-venous hemofiltration (CAVH). More recently, continuous veno-venous hemofiltration (CVVH) has been used to reduce the complications associated with such issues as hemodynamic instability and need for arterial access.
Hemodialysis and hemofiltration can be used to remove excess fluid from a patient, especially in patients whose kidneys have failed. The term “Renal Replacement Therapy” generally refers to all forms of dialysis, solute and fluid balancing therapy. Another category of patients affected by fluid overload are those with congestive heart failure (CHF). Patients suffering from CHF have weakened hearts that are unable to provide normal blood flow to the kidney and organs of the body. CHF patients may have normal kidneys, but lack sufficient blood flow to maintain proper kidney functions of removing excess fluid, e.g., water, from the body. The build-up of excessive fluids due to inadequate kidney functions further increases the blood pumping load on the heart, which is already suffering from CHF.
Renal replacement therapy performs two primary functions: ultrafiltration (removal of water from blood plasma), and solute clearance (removal of different molecular weight solid substances from blood plasma). The filter utilized, also called hemofilter or “dialyzer”, can be set up to perform either or both of these functions simultaneously, with or without fluid replacement. Similarly, the various modes of renal replacement therapy relate to whether fluids, solutes or both are removed and whether fluids are replaced. “Clearance” describes the removal of substances, both normal and waste product, from the blood whether by kidney function or during renal replacement therapy.
Dialysis is the diffusive transfer of small solutes out of a blood plasma compartment by diffusion across the membrane itself. It occurs as a result of a concentration gradient, with diffusion occurring from the compartment with higher concentration (typically the blood compartment) to the compartment with lower concentration (typically the dialysate compartment). Since the concentration of solutes in the plasma decreases, clearance is obtained, but fluid may not be removed. Ultrafiltration can be combined with dialysis.
Hemofiltration is the combination of ultrafiltration and fluid replacement, typically in much larger volumes than needed for fluid control. The replacement fluid contains electrolytes, but not other small molecules. Since the net effect of replacing fluid without small solutes and ultrafiltration of fluid with small solutes results in net removal of small solutes, clearance is obtained.
Existing renal replacement therapy machines and specifically those used in acute setting to perform (Slow Continuous Ultrafiltration) SCUF and CVVH therapy were designed to primarily perform hemofiltration and hemodialysis, not merely fluid removal. Blood is composed of cellular components suspended in the fluid component called plasma. Water is the primary constituent of plasma in which physiological solutes such as sodium and potassium are dissolved. Also, in plasma, larger molecules, such as proteins and blood cells, are suspended. Hemofiltration and hemodialysis remove solutes (and some larger molecules) in addition to fluid removal. Ultrafiltration relates to fluid removal from blood, and does not remove solutes or larger molecules.
Ultrafiltration and hemofiltration operate primarily by convection. In hemofiltration, a solute molecule is swept through a filter membrane by a moving stream of ultrafiltrate. Proteins and blood cells are retained in the blood by the membrane. In patients with renal failure, renal replacement therapy, such as hemofiltration or dialysis, removes undesired solutes. In renal replacement therapy, vital elements such as electrolytes are also removed from the blood and need to be replaced to maintain electrolyte balance. Thus, hemofiltration and dialysis treatments usually require fluid replacement. In contrast, ultrafiltation does not remove substantial amounts of electrolytes and solutes.
During hemofiltration solute removal is entirely dependent on convective transport. Hemofiltration is relatively inefficient for solute removal, as compared to dialysis. Hemodialysis allows the removal of water and solutes by diffusion across a membrane in the direction of the concentration gradient. Diffusion transfers solute molecules across the membrane in the direction of the lower solute concentration at the rate inversely proportional to the molecular weight.
Hemodialysis requires a large filter membrane surface to enable effective solute clearance by diffusion. Hemofiltration requires large amount of ultrafiltrate to be transferred across the membrane to remove a relatively small amount of solute. This is a consequence of convection being an inefficient method of solute transport. Large amounts of fluid such as 1 to 4 liters per hour (L/hour) are continuously being removed during CVVH. The resulting loss of water and electrolytes are immediately dangerous to the patient. To maintain fluid and electrolyte balance, equally large or slightly lower amount of replacement fluid is infused into the patient. Replacement fluid is thus added into the extracorporeal blood circuit before or after the filter.
Ultrafiltration utilizes extracorporal blood filters to remove fluids from blood, where the filter generally includes a blood passage having input and output ports, a filtered fluid discharge port and a finely porous membrane separating the blood passage and the ultrafiltrate of filtrate discharge port. Ultrafiltration involves the convective transfer of excessive fluid out of the blood plasma from the blood passage, through pores in the membrane, and to the discharge port of the filter. The pores filter electrolytes and small and middle sized molecules (up to 20,000 to 30,000 daltons) from the blood plasma. Importantly, since the concentration of small solutes is the same in the ultrafiltrate as in the plasma, effectively, no clearance of solutes from the blood plasma occurs during ultrafiltration. Accordingly, the ultrafiltrate output from the filter is substantially all fluids, e.g., water, and is relatively free of solutes.
2. Limitations of Existing Devices for Ultrafiltration
Dialysis machines historically used sets of disposable components that are assembled of various parts from different manufacturers. This allowed flexibility but had certain disadvantages. Joints between component parts may leak, allow ingress of air and facilitate blood clotting. High skill was required from hospital nurses and technicians to assemble tubes, connectors, filters and accessories and then load them correctly into pumps, bubble detectors, pressure sensors and other interface elements of a dialysis machine. In the setting of a chronic dialysis center such practice was acceptable. However, in an acute setting, such as an Intensive Care Unit (ICU) of a hospital, the complexities of dialysis machines became an impediment.
As a result, use of mechanical fluid removal in the ICU, Emergency Rooms and general floors of a hospital has been limited. One United States manufacturer recently released sophisticated apparatus marketed under the tradename “Prisma”™ by Hospal-Gambro. It uses an integrated set of disposable dialysis components in which tubing, filter and accessories are bonded together and no assembly is required. The filter, sensor interfaces and four dedicated pump segments (for blood, dialysate, replacement solution and effluent) are mounted on a flat plastic cartridge to simplify the loading of the dialysis pumps. The Prisma™ machine is advertised as “an integrated system for continuous fluid management and automated renal replacement therapy blood.”
While Prisma™ has been a significant advancement in the state of the art and has enjoyed wide adoption, it has its deficiencies. One deficiency is that, although the Prisma™ set of disposable dialysis components is continuous and bonded together, it does not present a smooth blood path but incorporates elements that create stagnant and slow moving blood zones. In such zones blood clots are likely to form. It also employs an interface to pressure sensors that is relatively inaccurate, unreliable and requires maintenance. There is a need for an improved design of the blood flow dialysis set that is simple to use, requires no maintenance or special training, and has improved performance over the existing set of disposable components for the Prisma™ machine.
In addition, the Prisma™ set does not integrate pressure sensors. Instead it integrates pressure “pods” shaped as domes. The interface surface of a pod is made out of silicon membrane approximately one inch in diameter. When mounted on the Prisma™ machine pods interface with the permanently installed pressure sensors that are the part of the machine. The interface is sealed by a rubber gasket so that the pod membrane serves as a lid on the pressure transducer cavity. When in operation, blood and other fluids flow through pods and come in contact with the membrane.
Pressure pods provide a means to measure the pressure of blood and other fluids flowing outside an interface surface. When the pressure inside the pod is increased the diaphragm stretches and thereby compresses the air inside a transducer cavity. As a result pressure in the bloodline or a fluid line is measured. The pod membrane serves as a barrier between the blood and potential contamination from environment, as is similar to the clinical invasive vascular blood pressure measurements. This method, although functional, has several deficiencies:                1. To be accurate pods have to be positioned perfectly when the pressure inside is atmospheric. Over time, if there is even a miniscule leak on the transducer side of the membrane, pod will creep and gradually stop transmitting pressure accurately because of the tension in the membrane.        2. Stretchable membranes and air filled transducer cavities add compliance to the circuit. Compliance is a delay in a pressure measurement due to the time required to stretch the pods and compress the air inside the pod cavity. Compliance is not desired since it makes the system less responsive to controls.        3. Pods filled with blood increase the blood-plastic contact surface and create stagnant zones with low blood flow velocity that facilitate clot formation. Because clots may form in the pods, the use of pods also necessitates the use of clot capture devices.        4. Pod domes have significant volume that increases the total extracorporeal volume of blood. This increased volume also increases the time that blood spends in contact with foreign materials. Altogether this increases risks of blood loss, hypotension and clotting.        